About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
April 29, 2004
The real news on the cancer front is in the post below, but I have a few other things to take care of tonight, too. Yesterday's post on Imclone's stock price was not well-received over on the IMCL message boards on Yahoo, where I've picked up several of the usual responses. They include the standard-issue Dark Suspicions that I'm one of the Evil Stock Bashers trying to scare The Little Guys into parting with their beloved Imclone, presumably so my top-hatted overseers can scoop it up for a song.
Well, folks, the guy with the top hat who was scooping up Imclone when it was cheap is Carl Icahn, more power to him. I don't work for him, sad to say. He bought the majority of his stake, several million shares worth, below $20, and he's for damn sure not buying in at $70 a share - in fact, he's probably selling his shares to you.
On a slightly higher plane, one comment sums up several others that I've received:
"These guys are clueless. (Erbitux) works against a growth factor common in numerous cancers. What they do not comprehend is the fact that if it works against one, it works against many; and if it works late stage, it works early and middle stage too. They value Erbitux based only on its approval, as if it will never receive any other indication approvals. Like I said, clueless."
I'd like to point out to this fellow and the other Yahoots that, unfortunately for this argument, I do drug research for a living. Blogging most certainly does not pay my bills; Big Pharma does. And among the therapeutic areas I work in is cancer, giving me a reasonable familiarity with the field. I can state, then, with some assurance, that the commentator above is full of fertilizer.
Yes, the epidermal growth factor receptor is indeed common in many cancers. But its importance varies widely in different tumor lines, and widely among different strains of what superficially appear to be the same kind of tumor. The same goes for all the other cancer targets you can name. A more accurate restatement of the above person's doctrine would be: If it works against one, it might work against some others. Or it might not.
We're only beginning to figure out the details, and - this is important - they're not going to increase Erbitux's market share when we do. Read the next post below for more on this. Erbitux will pick up some off-label sales, sure, but it's not going to end up with a long list of approved indications that will push it into the stratosphere.
And why not? Well, don't let those shimmering waves of greed blind you to the facts: in their clinical trials, Imclone, BMS, and Merck-Darmstadt carefully picked the tumor types that would be expected to give the most robust response. That's how you get a drug approved, by going to the agencies with the best data you can get. Erbitux has already been tested in the areas where it's likely to gain the most market share and make the most profit.
And there are plenty more drugs breathing down its neck. Go on and hold that IMCL, guys, go ahead and mortgage the house to buy some more. Maybe you'll watch it go to $150; stupider things have happened. But I think that the odds are that you're going to wish you'd taken your profits in 2004.
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The big news today was the Thursday release of two papers, one from Science and one from the NEJM, from two teams who have done something that we in the drug industry have long been working on and expecting, with equal parts anticipation and fear.
AstraZeneca's drug Iressa, like many other chemotherapies, varies widely in its effectiveness. Some lung cancer patients have experienced dramatic, life-saving remissions, while others have shown no improvement at all. Everyone's suspected that there is some genetic difference responsible for this, and now it's been found. The responders tend to have a set of mutations in their version of Iressa's target protein, EGFR, as compared to the nonresponders. So here it is - the pharmacogenomic era has started for real.
I've written about this issue before. As I've said, this is going to mean, eventually, that we're going to need a lot more cancer drugs as the various forms of the disease are categorized. Of course, the best way to categorize them is for us in the drug industry to keep on delivering therapies that don't work as well as we'd hoped, which is a little nerve-wracking. There's no way we could have predicted these EGFR mutations from first principles, for example. But we're going to end up with a lot more discrete targets to work on.
And as we find drugs for them, the clinical effects are going to be dramatic. If we can keep it up, people are going to gradually, over the next decades, stop dying from cancer. It'll be one tumor line at a time, but I think it'll happen. In an aging population, that's going to be the next thing to a miracle.
But finding all these drug subtypes is going to be tough, and expensive - and the kicker is that we're no longer going to have as large a patient population to sell them to. The not-so-well-kept secret of cancer therapy is that everyone has, for a long time now, ended up prescribing every drug for almost everything. Because you never know, it might work, and what do you have to lose after a certain point? But that whole market regime is going to collapse eventually, and the first tremor just shook today.
This is going to be "creative destruction" in its purest form, because something's going to have to change drastically. We drug companies are going to have to deliver drugs that (at least as far as we can see now) are going to cost just as much to find and develop as the ones we have today - and maybe more. But we're only going to be able to sell them to a fraction of the market that we can now, and this in a world where people are already having rug-biting fits about the prices we charge.
There's celebrating going on in the drug industry tonight - we finally know why a compound really works in some people! We know exactly who to sell the drug to! But there a lot of nervousness, too, because now we also know exactly who we can't sell it to, either.
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April 28, 2004
It's been a wild time recently in the oncology field - well, not so much scientifically as financially. OSI took a huge leap the other day on good clinical news about Tarceva, the drug they're developing with Genentech. I'll gloss over the fact that I owned OSI stock at one point, and sold it in the 30s. Watching it go straight up to 90 in one day caused me a bit of a twinge, although I really don't think it has any business being that high. If I had still owned it, I'd have been knocking over things on my desk trying to get to the phone to sell my shares.
To further illustrate the fact that I should not be managing my own hedge fund, readers may recall that I was short Imclone stock earlier this year. I shorted at $40, and got out in March at $46, having been first ahead and then behind on the position. By the time I got out, the famous Erbitux had been approved, and it looked as if people were going to allow themselves to believe a lot of good things about its prospects.
That they have. The stock hasn't pulled an OSIP, at least not yet, but there's been a lot of sustained buying. As of today, Imclone stock is around $70, and who knows how far it'll go? After all, the same mindset that takes it to that price from $40 is perfectly capable of going to $100 from here. No problem at all - hey, on a percentage basis, that's less of a haul than what's been accomplished so far. I'm glad that I decided not to stand in front of that particular train.
But what kind of track are the current buyers standing in the middle of? Guys, Erbitux is a drug that does some good for some people with some kinds of tumors. There's nothing wrong with that at all - in fact, it's a valid description of every form of cancer therapy on the market. But there are a lot of interesting therapies out there already, and there are a lot more coming. An antibody that costs thousands of dollars a month cannot possibly rule that world, not with that kind of efficacy. I wholeheartedly agree with Charly Travers over at the Motley Fool, who says:
"I really have to wonder who is buying this stock and just what the heck they are thinking. ImClone's Erbitux is approved as third-line therapy in patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor. Taking into account this population size and assuming 30% market penetration and a drug cost of $10,000 per month, I arrive at a peak U.S. sales figure near $600 million. With a 39% royalty on those sales due to ImClone from partner Bristol-Myers Squibb (NYSE: BMY), ImClone's revenues would be near $225 million. Adding in a royalty on European sales from partner Merck (NYSE: MRK), my ballpark figures for peak ImClone revenues from worldwide sales of Erbitux are $275 million to $325 million."
Problem is, that means that Imclone is already priced at between 50% and 100% higher than it probably should be at its peak. When you buy a stock like this, aren't you buying it in the expectation of growth? Where on earth is that going to come from? Today's buyers can only hope for people who can't do math to come along and relieve them of their shares. More likely, the mathematically impaired are already in there buying right now, which will gradually limit the target audience for a profitable resale to either pretechnological tribesmen or the crews of recently arrived UFOs.
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April 27, 2004
In the wake of the Sanofi-Aventis merger, there have been comments in the press about how Sanofi's research labs were more productive. Aventis, by contrast, is said to have been relatively stodgy and lacking in results.
It's true that Sanofi has done very well for itself. They've worked in a number of interesting therapeutic areas, and they've taken good advantage of their opportunities. Why they would want to ruin things, disrupting research for years in a quest to turn the company into an elephant, is another question.
But although I haven't had good things to say about Aventis in the past, I have to stick up for them a bit. I've had occasion to look over their patent activity in recent years, and they've been working on some interesting things. They've gone after targets where they would have been first in class, and they've worked on a lot of different ideas. But their compounds just haven't worked out.
How much of that is due to inadequate research, and how much is due to luck? It's impossible to know. Really good companies can have runs of terrible fortune (talk to Merck about what 2003 was like), so it's hard to prove that Aventis's pipeline is weak because they're doing a bad job. Overall, you'd think that they would have more to show for all the time and money, but we can all fill out a whole list of companies that fit that description.
What I think is certain, though, is that being merged won't help Aventis get things to work much better - not for years, if ever. And it sure won't help Sanofi to jump on research ideas any faster. Giant companies aren't too good at that. And if this merger-of-equals thing goes wrong, way too much effort is going to go into turf wars for anything good to happen. You don't have to look far for examples of that, either.
The only thing that will get bigger and better is the sales force, which is how Pfizer's huge growth has been designed. I regard Pfizer as basically a marketing machine, and perhaps FrancoPharma, or whatever this ungainly beast will be called, is hoping to be another one. That'll be sad. You'll have to keep in mind that this is someone from research talking, but I don't think that's a very high target to aim for.
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April 26, 2004
. . .and I fear thou play'dst most foully for it. So Sanofi is really going to get Aventis, and the French government is really going to get their mighty standard-bearer in the drug industry. Bonne chance, guys. I'm not a fan of big drug-company mergers to start with, and this one seems particularly pointless. The Wall Street Journal's coverage sums it up as far as I'm concerned:
"From the start, the battle for Aventis was as much about France's desire to create a home-grown national champion in the pharmaceutical industry as it was about shareholder value and business sense. . .France's intervention in the takeover battle, which runs counter to the free-market principles espoused by the European Union. . ."
"Lip service" translates into all the EU languages, that's for sure. Since when has France ever really been interested in such an Anglo-Saxon concept as a free market? Not when there's national pride at stake, anyway. Look, I understand the desire to have something to point to, to have companies from your own nation be influences on the world. But will this new company be something to be proud of?
The odds are against it. Now that they have this big new Frenchoid drug company (remember, there's a big German contingent, ex-Hoechst), what are they going to do with it? As I've said before, the only way to make the deal make sense, as far as I can see, is for some people to lose their jobs. You know, like most mergers. And since we're certainly not going to have any job cuts in France, and since the German unions have locked their positions up, what's left? (Well, the former Hoechst site in Bridgewater, NJ is left, for one - but if they cut there, this new Francopharma will be doing the complete opposite of all the other major European drug companies.)
Novartis came in at the last minute, but declined to make a bid, which I think was smart of them. Saves a lot of suit jackets from having to be pressed after the French got through twisting their arms, anyway. Novartis's entry may well have driven up the price of the eventual deal, though, and seeing a competitor overpay for an asset must not upset them much, either. If I were more conspiratorial, I'd wonder if that was the whole point of their involvement. . .
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April 25, 2004
I'm not sure if I've told this story before - perhaps on my previous blog. The memory is with me so vividly that the retellings run together.
I've never liked hydrogenation rooms. For my non-lab audience, that's where we keep the equipment for running reactions in pressure vessels under hydrogen gas, always with some sort of metal catalyst to make the hydrogen come in and reduce things. It's about as close to witchcraft as modern organic chemistry gets.
And it's just those ingredients that make me nervous. Big metal cylinders of hydrogen gas can't help but bring to mind visions of the Hindenberg, for one thing. If something fails on the apparatus, it generally fails with spraying, fizzing, and/or flames. And any hydrog room that's been around a few years invariably picks up black residues of spilled catalyst everywhere. It's in the cracks of the lab bench and in the fittings of the equipment.
You want to be careful with that stuff. Most of the time, we use powdered charcoal impregnated with palladium or platinum, which looks like, well, charcoal. But under the right (um, wrong) conditions, it can come to life like you wouldn't believe. In the presence of hydrogen gas and some air, such as when you mess up and open the flask, the powder gets so hot it glows bright orange. It looks like it's just come out of a furnace, and that's about when it ignites your reaction solvent. Then you might as well get out the hot dogs and suntan lotion, because the fireworks are going off already.
Once about thirteen years ago, I was in my company's old hydrogenation room getting a balloon full of the gas to take back to my lab. You can run less vigorous reactions under just that much gas, so there's generally some fitting for people to fill things up to go. In this case, you opened up the valve near the gas cylinder just a crack, and then opened up the needle valve near the balloon a lot.
Or, anyway, that's how we'd been doing it. When I got there that afternoon, someone had just decided that they liked it better the other way around, where you just barely dinked the balloon takeoff valve. News to me. I stuck my balloon assembly on, opened the valves up the way I was used to, and KA-BLAM!
Off goes my whole balloon and tubing rig, flying off the fitting from the blast of gas. And up I went, straight into the air, with my hair, I swear, standing straight out from my head in some sort of mad-scientist perm. My adrenal glands hit the Emergency Squirt button and dumped their entire load of adrenaline into my bloodstream, convinced that at long last a sabretooth had shown up at the mouth of the cave.
I landed on my toes and bounced back up like a rubber ball. A videotape of my actions would be worth watching; I've often been sorry that I don't have one. I was pinging around the room kicking at the cabinets, waving my arms and gibbering obscenities. It took a couple of circuits of the place before I could slow down enough to be sure that I had all my extremities attached. I hate hydrogenation rooms. . .
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April 23, 2004
I've noticed many visitors hitting the category topics over there on the right side of the page. Unfortunately, some of those headings don't have any posts in them yet, because we're still transferring the contents of the old site over here.
As of this writing, we only have about the last fifty posts or so, but I'm a much wordier guy than that. The usefulness of the topic links will increase as time goes on, so be sure to give them a try again in a few weeks. They'll fill out into their intended glorious (cough) shape.
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April 22, 2004
I mentioned the other day that not everything in that Stuart Schreiber interview sounded sane to me, (although more of it does than I'd expected). The interviewer, Joanna Owens, asks him to expand on a statement he made about ten years ago: famously (in some circles, at any rate) Schreiber said that he wanted to - and thought that eventually he could - produce a small-molecule partner for every human gene.
A worthy goal, to be sure, but a honking big one, too. To his credit, though, Schreiber isn't making light of it:
". . .that challenge understates what we really want to do, which is to use small molecules to modulate the individual function(s) of multifunctional proteins, activating or inactivating individual functions as necessary. This is one of the differences between small molecules, for example, and the knockout of knowckdown technologies, where you inactivate everything to do with the protein of interest."
Note how things have appropriately expanded. There are a lot more proteins than there are genes (a lot more, given the surprisingly lowball figure for the total size of the human genome), and the number of protein activities is several times larger than that. He's absolutely right that this figure is the real bottom line. But here comes that Muhammed Ali side of his personality:
"Small molecules allow you to gain control rapidly, and can be delivered simply but, most importantly, we've shown that we can discover molecules that only modulate one of several functions of a single protein. . .(the scientific community has) identified 5000 out of the required 500,000 small molecules, which is similar to where the Human Genome Project was in year two of its 12-year journey. That might be a useful calibration - optimistically, we're ten years away."
Midway through that paragraph is where I start pulling back on a set of imaginary reins. Whoa up, there, Schreibster! Let's take the assumptions in order:
Small molecules allow you to gain control rapidly. . . Compared to transcription-level technology, this is largely correct. But the effects of small-molecule treatment often take a while to make themselves known, for a variety of reasons that we don't fully understand. The problem's particularly acute in larger systems - look at how long it takes for many CNS drugs to have any meaningful clinical effect. And these complex systems have other weird aspects, which make the phrase "gain control" seem a bit too confident. U-shaped dose-response relationships are common. Look at what you find in toxicology, where you see threshold effects and even hormesis, with large and small doses of the same substance showing opposite effects.
. . .and can be delivered simply. . . Well, when they can be delivered at all, I guess. But there more of them that come bouncing back at us than we'd like. In every drug research program I've been involved with, there are plenty of reasonable-looking compounds that hit the molecular target hard, but then don't perform in the cellular assay. You can come up with a lot of hand-waving rationales: perhaps the main series of compounds is riding in on some sort of active transport and these outliers can't, or they're getting actively pumped back out of the cell, or they hit some other sinkhole binding site that the others escape, and so on. Figuring out what's going on is an entire research project in itself, and rarely undertaken. Every time someone tells me that drug delivery is simple, I can feel my hair begin to frizz.
. . .we've shown that we can discover molecules that only modulate one of several functions of a single protein. . . True enough, and a very interesting accomplishment. But the generality of it is, to put the matter gently, unproven. It would not surprise me at all if there turn out to be many proteins whose functions can't be independently inhibited. The act of binding a small molecule to alter one of the functions would cause the other ones to change. And a bigger problem will be distinguishing these effects from the consequences of actually taking out that first function cleanly: how will you know when you've altered the system?
. . .which is similar to where the Human Genome Project was in year two. . . True, but that and forty dollars will get you an Aldrich Chemical can opener. The comparison isn't just optimistic - it's crazy. The problems that the genome sequencers faced were engineering problems - difficult, tricky, infuriating ones, but with solutions that were absolutely within the realm of possibility. Faster machines were made, with more computing power, and new techniques were applied to make use of them.
But as I've been saying, I'm not sure that the Maximum Inhibitor Library that Schreiber's talking about is even possible at all. Don't get me wrong - I hope that it is. We'll learn so much biochemistry that our heads will hurt. But its feasibility is very much open to question, to many questions, and we won't even begin to know the answers until we've put in a lot more work.
+ TrackBacks (0) | Category: Biological News | Drug Assays | Drug Development
April 21, 2004
I spent my morning wandering through the labs with an inventory sheet in my hand, muttering about what kind of research organization this is if nobody has any triflic anhydride, damn it. For the non-chemists in the audience, this is pretty reactive stuff. It turns alcohols into trifluoromethanesulfonate esters, which nomenclature has been understandably shortened to "triflate" over the years.
We do a lot of these reactions known as nucleophilic substitutions, where one group basically comes in and kicks another one out. Some of them will only work well when you have the most reactive partner you can find, and triflate is God's own leaving group. Once your alcohol has been converted, the sulfonate ester will make way for just about anything you can toss into the flask. In many cases, you don't spend much time purifying or isolating the triflate - just wash the reaction a bit, evaporate the solvent, and roll on to the next step, which is what I was doing today.
Once I found the reagent, that is. Turns out that I was only partially a victim of bad inventory control, though. I was also feeling the effect of not working in the lab as much as I used to. They used to - back in the old days, sonny - package triflic anhydride in glass ampoules. Those are a bit of a pain, because you need to snap them open, which process either works just fine or really not fine at all. The smaller ampoules come pre-scored around their narrowed neck, but the larger ones (say, fifty grams) have to be touched up a bit first with a metal file, unless you're a real buckaroo. (As a side annoyance, this is pretty much the only use most organic chemists have for a triangular metal file, so it can be hard to track one down.)
Once you've opened the thing, you have to find a new container for the leftover reagent. Of course, if there were a good way to store the stuff in a regular container, they wouldn't ship it to you in an ampoule, now would they? Triflic anhydride, and its hydrolysis product, the viciously strong triflic acid, are notorious plastic-eaters and cap-softeners. I'd estimate that a solid majority of the stuff sold every year has gone to waste. People come back in a couple of months and find the stuff looking like used lawnmower oil, so out it goes.
Progress has been scurrying along, though, while I wasn't watching, and it turns out that they now sell the reagent in a regular bottle. The cap is made of some hardy high-density polymer, seemingly impervious to the nastiness it contains. Doubtless I looked right at some of these in the labs where I was searching, not realizing that my mental picture was now out of date. Trifluoromethanesulfonates themselves, though, never go out of style.
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April 20, 2004
The April issue of Drug Discovery Today has an intriguing interview (PDF file) with Stuart Schreiber of Harvard. Schreiber is an only partially human presence in the field, as a listing of his academic appointments will make clear: chairman, with an endowed professorship, of the Department of Chemistry at Harvard, investigator at the Howard Hughes Medical Institute, director of the NIH's Initiative for Chemical Genetics, faculty member of the joint Harvard/MIT Broad Institute (a genomic medicine effort), affiliate of Harvard's Department of Molecular and Cellular Biology and Harvard Medical School's Department of Cell Biology, member of Harvard's graduate program in Biophysics and the medical school's Immunology Department, a player in the early years of Vertex, founder of ARIAD Pharmaceuticals and Infinity Pharmaceuticals, and founding editor of Chemistry and Biology. (What other name would the journal have?)
Schreiber is extremely accomplished and intelligent, but he can also be quite hard to take. A powerful pointer to this tendency comes when the interviewer asks him about who's been his greatest inspiration - he leads off with Muhammed Ali and Neil Cassidy, and for better or worse, that's just about the size of it. Mix those two together, give the resulting hybrid a burning interest in chemical biology and a chair at Harvard, and there you are.
I've not met him personally, but I've heard him lecture more than once. The first time I saw him, he was speaking on one of his big stories from past years, the immunomodulator FK-506. He hit the afterburners during the first slide and ascended into the stratosphere, leaving us ground-based observers with only a persistent vapor trail. Slide after slide came up, densely packed with years of data in a punishing, torrential rush - after a while, people in the audience were clutching their heads as their pens clattered to the floor. Some of my readers will, I think, have had similar Schreiberian experiences.
And the guy has no problem with saying just what's on his mind, although if I had those faculty positions, I'd wouldn't be feeling too many restraints myself. It's a mixed blessing. Some of what he's got to say is very sensible, even if no one else feels like saying it in so many words, but he can also come across as divorced from reality and impossibly arrogant. I would have to think that a post-doctoral position with him would be a rather stimulating experience, which would doubtless take place during days, nights, weekends, major and minor holidays, and probably during periodic flashback dreams in the years to come.
The interview starts out by asking Schreiber what he thinks of the new NIH Roadmap initiative. He sounds the alarm, correctly, about one thing it seems to emphasize:
". . .what is perhaps surprising to some people is how much emphasis the NIH has placed on small molecules and screening in an academic environment. A meeting with some senior pharma industry executives made me realize that there are many people who are unhappy with this activity. When I went back and read what is being proposed, some of the language suggests that the plan is to fund early drug discovery and development in an academic environment.
Yet some of the language also suggests that the Roadmap is about a parallel process of using chemistry and small-molecule synthesis and screening to interrogate biology. In this model, a parallel set of techniques is involved but the overall goals are very different. I am equally concerned as the pharma industry if the Roadmap were to place too much emphasis on the first model, because I think that a focus on drug discovery in academic would represent a missed opportunity. Sending the message to groups of industry-naÔve biologists and chemists that they should now try to discover drugs in their labs could be problematic for a variety of reasons."
He's right on target there, I have to say. And what does this do to the arguments some people make that just about all the research the drug industry does is ripped off from NIH-funded work? (I've mentioned this topic before; as we get the archives working again I'll group those posts together with this one.) Schreiber goes on to point out that drug development works completely differently from academic research, and that mixing the two might well end up compromising the strengths of each.
Academia should do what it does best: exploration, discovering new islands and continents of knowledge that no one even knew were there. We in industry can do some of that, but our strong suit is finding concrete uses for such discoveries. We're good at doing the detail work of developing them into something that works feasibly, reproducibly, safely, and (dare I mention) profitably. Getting all those to happen at the same time is no mean feat, as any engineer or applied-research types will tell you at length.
I'll have more to blog on the Schreiber interview; not everything he says in it is quite so sensible. But this point was worth some craziness. I'd like to take some of the folks who try to tell me that the whole pharma industry is some sort of profit-seeking leech on the NIH-funded world and lock them in a room with the guy and a couple of projectors. As long as I could be around as his audience staggered out, groping for painkillers and rubbing their eyes. . .
+ TrackBacks (0) | Category: Academia (vs. Industry) | Drug Development
April 19, 2004
I had a question recently about why some chemical elements don't appear much in pharmaceuticals. Boron was one example - the first boron-containing drug (Velcade, from Millennium) was approved just recently.
But it hasn't been for lack of trying. Starting in the 1980s, several drug companies took a crack at boronic acids as head groups for protease inhibitors. Big, long, expensive programs against enzymes like elastase and thrombin went on year after year, but no one could get the things to quite work well enough. In vitro they ruled - a good boronic acid is about as good as an enzyme inhibitor can be. But in vivo they had their problems, with oral absorption and cell penetration leading the way.
As far as I'm aware, there's no particular tox liability for boron. Things like boric acid certainly don't have a reputation for trouble, and we don't take any special precautions with the air-stable boron compounds in the lab. It'll be hard to make any case, one way one another, based on the Velcade data, since the drug's mechanism of action (proteosome inhibition) has a lot of intrinsic toxicity anyway. (There's the anticancer field for you - there aren't many other areas where a target like that would even be considered.)
I think self-censorship is why there aren't more boron-containing structures out there. We don't spend much time looking at the compounds seriously, because everyone knows the problems with boronic acids, and no one wants to be the first to develop a different boron-containing functional group, either. "Why be the first to find a new kind of trouble?", goes the thinking. "Don't we have enough to worry about already?"
+ TrackBacks (0) | Category: Odd Elements in Drugs | Toxicology
April 18, 2004
The first comment to the original March of Folly post below mirrors the e-mail I've received: the people's choice for the technology most-likely-to-be-embarrassing is. . .(rustling of envelope): RNA interference.
There's a good case to be made for that, and it doesn't contradict my oft-stated opinion that RNAi is going to be good for one or more Nobel prizes. The big challenge will be how to divide things up correctly - we may well see some spillover into Chemistry from the Medicine/Physiology category. Believe me, there are several folks who should keep their eyes open for discount fares to Stockholm. This will probably happen in about five years or so, given the usual pace of the Nobel folks.
But industrial enthusiasm for RNAi may well have gotten out of hand in the last year or two. There are a number of small companies frantically trying to take the technique into the clinic; the whole thing reminds everyone of the heyday of antisense therapeutics. Remember antisense DNA? People are still out there trying to make it work, but it's been a lot harder than anyone would have wanted to believe. If you'd been able to show folks the future back in the late 1980s, a bunch of venture capitalists would have had rug-biting fits.
And RNA-based therapies suffer from almost exactly the same problems, and for the same reasons. Delivery of the molecule and its stability once dosed are going to be very tricky. One of the first things being targeted is macular degeneration, because the inside of the eye is a rather tranquil pond, pharmacokinetically speaking, and the cells there are known to take things up rather freely. But once you get out of that best-case situation, well, good luck. With any luck, RNAi might be able to adapt a successful antisense technique - if someone finds one.
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Pharmacokinetics
April 16, 2004
It's a relief to finally be able to post again. My previous platform ran into a major glitch last week, and it was only after a few days that I realized that none of my new posts were getting through. So here's the new site, run from a spiffy Movable Type interface.
That means that comments are now available, and I'm categorizing all my past posts as they get grandfathered in. All the rants about drug pricing, for example, will be available in one place for those who feel a dearth of spleen in their lives.
My apologies for leaving everyone hanging. We now proceed with our regularly scheduled weblog. . .
(Note: the blogroll is coming back, too, in pieces - this will give me a chance to update it and add a number of worthy sites I've been meaning to list. Any other features or questions, just comment or drop me a line. MT will do everything short of emptying the cat's litter box.)
+ TrackBacks (0) | Category: Blog Housekeeping
April 15, 2004
Thinking about molecular modeling, as I did in the last post, brings up another topic: when you go back to the late 1980s, in the real manic phase of the technological hype, what brings you up short is realizing that these folks were planning on doing all this with 1980s hardware.
That puts things in perspective. Here we are in 2004, and we still can't just sit down and design a drug from first principles. Don't believe anyone who tells you that we can, either - if that were possible, there would be a lot more drugs out there. I'm not saying that molecular modeling never makes a contribution (I know better, and from personal experience.) It's just that it hasn't (yet) caught up to the hallucinations of fifteen or twenty years ago, which is entirely the fault of the people who were doing the hallucinating.
You can make the same comments about other waves of hype that have broken over the pharmaceutical world (combinatorial chemistry comes immediately to mind.) What I'm wondering is: what's the hype of today? There's bound to be a hot new idea that's going to solve our problems, but will end up changed beyond recognition after twenty years of the real world. Any votes on what's going to look faintly ridiculous to us in 2024? As you'd guess, I have some candidates of my own. . .
| Category: Drug Industry History | In Silico
April 14, 2004
Molecular modeling is a technology with a past. Specifically, it's a past of overoptimistic predictions (often made, to be fair, by people who didn't understand what they were talking about.) Back in the late 1980s, when I started in the drug industry, modeling was going to take over the world and pretty darn soon, too. Several companies were founded to take advantage of this brave new world that had such software in it, and they raised serious money with tales of how they were just going to zzzzzip right to the drug structures. No dead ends, no detours, no cast of thousands - just a few chemists standing by to make the structure as it printed out for them. This has not quite worked out.
For those not in the business, modeling is the attempt to figure out molecular shapes, properties, and interactions by computation. There are many levels, some more successful than others. The ones I'm speaking of involve predicting three-dimensional shapes of molecules (and their target binding sites), and deciding which ones are more likely to fit well. It sounds like just what we need. It also sounds reasonably doable, in the same way that Hercules was probably told at first that he was going to just have to round up a few stray animals.
Predicting the shapes involves modeling the individual chemical bonds, and the interactions as the atoms and functional groups rotate around them, banging into each other or sticking through various forces. Originally, these things were calculated as if they were in interstellar space, with nothing around them. Later (and ever since) a number of methods to add some real-world solvent effects have been tried.
Another set of programs evaluates intermolecular fits, trying to work out the energies in play when a drug molecule slides into its binding site. Many tricky refinements have been added to those packages over the years, too, taking advantage of the latest insights into how various groups stack, pack, and interact.
And often enough, it just isn't enough. Many times the structures we have for our binding sites aren't accurate - the best ones are from X-ray crystallography, and plenty of good stuff just doesn't crystallize. (There are other cases where the crystal structure doesn't bear much relation to what's going on inside the real system, too, just to keep everyone on their toes.) Modeling goes haywire for all kinds of reasons.
One of the companies that emerged back in the change-the-world era of modeling was Vertex, up in Cambridge. It was founded by Joshua Boger, a Merck chemist who wanted a piece of the new thing and wasn't sure that Merck was taking it seriously enough. Well, coming soon in the Journal of Medicinal Chemistry (it's in the web preprint section now) is a paper from Vertex which gives us all some idea of why things didn't work out quite as planned.
The Vertex guys went back over about 150 cases, and found that in the majority of them, the structure of the small molecule in its binding pocket wasn't the structure you would have predicted as the best (read: lowest-energy.) In many of them, it isn't even close. You'd literally never have picked some of these conformations to start a modeling effort - they look very disfavored, and if you're going to pick things that far from the ground state then there's no end to it. The number of structures gets worse very rapidly as you move away from the local energy minima.
We in the business had suspected as much, and everyone knew of an example or two, but this is a quantitative look at just how bad the situation is. When you add in the cases where the binding site changes its conformation unexpectedly in response to the ligand, it's a wonder that any modeling efforts work at all. (Frankly, in my experience, they mostly don't, but I'm willing to stipulate that my experience has been more negative than the average.)
I like to say that molecular modeling is a magic wand, one that we keep waving in the hope that sparks will eventually start to shoot out of it. Someday they will. But there's a lot more hard work ahead, and no shortcuts in sight.
| Category: Drug Industry History | In Silico
April 13, 2004
You've probably heard of the hypothesis that a reasonable amount of dirt is good for you, especially in childhood. (My kids are certainly taking no chances.) The idea is that the immune system needs a certain amount of challenge to develop properly, so trying to live too antiseptic a life is a mistake. I think that this is very likely correct, and it turns out that it's especially correct if you're a zebrafish.
Not many of my readers are zebrafish, at least as far as I can tell from my referral logs, but they're an influential demographic. Danio rerio isn't as well known outside biology as say, the fruit fly, but it's a workhorse model organism for vertebrate development. Zebrafish are small, fast-growing, and the embryos are nearly transparent in their earlier stages. (Xenopus frogs share these characteristics, and have their partisans, too.)
The March 30th issue of the Proceedings of the National Academy of Sciences, with a Warholian zebrafish cover, features a study from Washington U. where the fish were raised under strictly aseptic (gnotobiotic) conditions. That's not easy to do, but if you make absolutely sure that no bacteria are present, it turns out that the embryos don't even develop properly. The defects are in the gut, which makes a lot of sense.
It turns out that colonization by normal intestinal flora is vital - zebrafish and their bacteria have become evolutionarily entangled. The bacteria actually induce some crucial gene expression by their presence, and the developmental program just doesn't have an aseptic default setting. There hasn't been an aseptic zebrafish since the beginning of biological time.
OK, these guys swim around in tropical pools, floating in a bacterial soup. But we're floating in one, too, just at a slightly lower density. Every part of a human body that can be easily (benignly) colonized by bacteria already is. Are there similar developmental effects in man? It wouldn't surprise me at all. No one's going to be running that exact embryo experiment, needless to say, but there are probably ways to sneak up on the answer using cell cultures. There's never been an aseptic human baby, either. . .although this is enough to make a person wonder about situations where a pregnant mother has had to take a long course of powerful antibiotics.
| Category: Biological News | Infectious Diseases
April 6, 2004
This morning brings the news, via ABC, that the recently discovered bomb plot in London involved a quantity of osmium tetroxide. That's a surprise.
I know the reagent well, but it's not what anyone would call a common chemical, despite the news story above that calls it "easily obtained." It's quite odd that someone could accumulate a significant amount of it, and it's significant that anyone would have thought of it in the first place. It's found in small amounts in histology labs, particularly for staining in electron microscopy, but that's generally in very dilute solution. If these people had the pure stuff, well, someone's had some chemical education, and probably in my specialty, damn it all.
The reagent is used in organic synthesis for a specific (and not particularly common) reaction, the oxidation of carbon-carbon double bonds to diols. I've done that one myself once or twice. OsO4 comes in and turns the alkene into a matched pair of alcohols, one on each carbon, and it stops there. Other strong oxidizing reagents can't help themselves - they find the diol easier to attack than the double bond was, and go on to tear it up further. There was a recent paper in the literature on the mechanistic details, actually, going into just why the osmium reagent stops where it does.
Unfortunately, the alkenes it could attack are unsaturated fatty acids and such, as found in lipoproteins and cell membranes. Exposed tissue is vulnerable. Breathing a large amount of the vapor can kill a person through irritation of the lungs, but it's not as bad that way as the better-known agents like phosgene. A bigger problem is the cornea of the eyes, and the reagent is mostly feared for its ability to bring on temporary (and in some cases, permanent) blindness.
There's no doubt in my mind that any terrorist with the stuff was going for that effect. Could it have worked? Well, it's a solid at room temperature, but a hot day will melt it. The stuff sublimes easily; it has a high vapor pressure. Just being around the solid crystals is enough to get you overexposed to the vapors. I don't know how much of the reagent these people had, but I tend to think (again, contrary to the ABC story) that an explosion would have dispersed it to the point that it was just down to irritant levels. I wouldn't want to find out, though.
If they were planning to use it in a non-explosive gas attack, that's another matter. But the vapors are said to be very irritating, with a distinctive chlorine-like smell - which I cannot verify, thank God. It's not like no one would have noticed that there was some nasty chemical in the air. I think that they could have done some damage, certainly. But what disturbs me more than the reagent itself is the thinking behind it. . .
| Category: Chem/Bio Warfare | Current Events | Toxicology
April 5, 2004
I've noticed that discussions of patent law really wilt my traffic something fierce, so I thought I'd go ahead and get another one out of my system now. Perhaps the effect isn't additive. (It'll serve me right if turns out to be nonlinear the other way).
One of the things that hits you when you start worrying about patenting chemical compounds is that there sure have been a lot of them patented. The number of compounds exemplified is pretty large all by itself, but it's just a roundoff error compared to the number that have been claimed. I've seen patent specifications that I swear would run well into the millions if every claimed variation were rung.
They aren't, of course. There's no way that they could be. The extra space is just breathing room, to try to keep the competition from coming too close to the good stuff. It's also to protect some of it for you if you happen to come across something else that's good after you file, but that's a two-edged sword - if you find it too much later, you've got a patent with years of its lifetime already expired, for one thing.
It's important to remember that these drug patents aren't just randomly distributed around the world of chemical structures, either. There are plenty of things that no one is going to be interested in patenting, because they're too reactive or toxic. And there are other structures that just lend themselves to drug discovery: piperidines, piperazines, biphenyls, imidazoles, and tricyclics are just a few that come immediately to mind. The patent space around those things has been trampled, plowed, clear-cut and strip-mined.
These things are all prior art for new patent applications to worry about. Exemplified, reduced-to-practice compounds are bulletproof prior art: if it's been described in the literature, you can't own it. You can claim a new way to make it, or a new use for it, but you can't claim the chemical matter. Section 103 of the patent code says that an invention has to be nonobvious, and you don't get much more obvious than something that's already there. But what about all those claims, those huge, inflated claim structures that reach well into the Kuiper Belt? Are all those off limits?
We'd be in big trouble if that were the case. After all, the problem gets worse each year, nonlinearly worse as the pace of research (and the pace of patenting) picks up. But there's a way to sneak into those putatively fenced-off reserves. If you turn to the MPEP, the patent examiner's manual, you find that "the fact that a claimed species or subgenus is encompassed by a prior art claim is not sufficient by itself to establish a prima facie case of obviousness." Good news, indeed.
For a patent examiner to reject a claim on the grounds of obviousness, the manual says that "it is essential that Office personnel find some motivation or suggestion to make the claimed invention in light of the prior art teachings. . .regardless of the type of disclosure, the prior art must provide some motivation to one of ordinary skill in the art to make the claimed invention. . ." And that's the key. Those massive edifices of claim language eventually have to get down to earth. As the claims roll on, page after page, they start narrowing down. A preferred embodiment of the invention is. . .a still more preferred embodiment. . .a particularly preferred embodiment. . .eventually you get down to what they really, really want to protect.
And legally, what they're doing is teaching you the invention. The claims teach toward the true invention, and the rest of the patent is supposed to teach you how to carry it out (including the "best mode" requirement I mentioned yesterday.) If you're claiming something that's way out in the fringes of the first forest of claims, then the rest of the patent is clearly going to teach away from it. And that means that you can get it for yourself.
There are complications. This is patent law; of course there are complications. It'll hurt your case if you're going for the same use as the original compounds. Your best chance there is to show that your compounds perform in some unexpected way, which the original patent claims clearly didn't anticipate. A less common way to break out of this situation is to show that the original patent's methods wouldn't even be able to produce some of the distant structures - if they don't teach how to make the structures, they can't have 'em.
So that's how it's done. That's not to say that patenting isn't getting harder all the time, because it is (after all, there are all those truly exemplified compounds piling up.) But at least it isn't getting impossible. Nothing a lot of time, effort, money, and legal resources can't attack, anyway.
| Category: Patents and IP
April 4, 2004
Not much time to post tonight. Things have been fairly busy in the research world, with the added burden of some patent filings and some evaluations of other filings from the competition. These only confirm to me that there is no way that I could possibly keep bread on my table as a patent lawyer.
Some of my co-workers might find that a bit odd, since I have the reputation at work of knowing a bit more than usual about the subject, for a medicinal chemist. But that just means that I know enough about it to be an irritant to the attorneys. I can't shake, while thinking about the legal issues, a feeling that all that mental effort could surely be put to some better use.
As no doubt it could, but only with some other species. As with any other field, there is no way to write the rules in such a manner that no one can get around them. Writing a patent is a deadly mixture of drudgery and, well, trickery. You're required to disclose the best mode for realizing your invention, and you'd better do it, too. But you're not required to mount a flashing neon sign pointing to it. And you have to exemplify the things that are at the heart of your claims, to reduce them to practice, as the lingo has it. But there's nothing that says that you can't exemplify lots of other things, too, during which you feel like a cuttlefish spewing ink.
Nope, it's not something I can do for long stretches. I enjoy brief visits into Lawyer Country, but I make sure that I have my return ticket in my pocket at all times. No doubt they'd find it easier if they didn't have to deal with us lab types so much, too. I won't ask; they'd tell me.
| Category: Life in the Drug Labs | Patents and IP
April 1, 2004
One of the main things I noticed when I joined the pharmaceutical industry (other than the way my black robe itched and the way the rooster blood stained my shoes, of course) was how quickly one moved from project to project. That's in contrast to most chemistry grad-school experiences, where you end up on your Big PhD Project, and you stay on that sucker until you finish it (or until it finishes you.)
My B.PhDP. was a natural product synthesis, and I had plenty of time to become sick of it. My project seemed to be rather tired of me, too, judging by the way it bucked like a mad horse at crucial stages. Month after month it ground on, and the time stretched into years. And I was still making starting material, grinding it out just the way I had two years before, the same reactions to make the same intermediates, which maybe I could get to fly in the right direction this time. Or maybe not. . .time to make another bucket of starting material, back to the well we go. . .
Contrast drug discovery: reaction not working? Do another one. There's always another product you can be making - maybe this one will be good. Project not going well? Toxicity, formulation problems? Everyone will give it the hearty try, but after a while, everyone will join in to give it the hearty heave-ho, because something else will come along that's a better use of the time. Time's money.
It keeps you on your toes. You have to learn the behavior of completely new classes of molecules each time - no telling what they'll be like. You dig through the literature, try some reactions, and get your bearings quickly, because you don't have weeks or months to become familiar with things. The important thing is to get some chemistry going. If it doesn't make the product you expected, then maybe it'll make something else interesting. Send that in, too. You never know.
| Category: Academia (vs. Industry)